Questions that spring to mind:
Why don't study models where AMPK is elevated show resulting weight/fat gain? Why does it tend to be the opposite?
If an organism is not "burning" (metabolizing) body fat, how do you propose the fatty tissue would be depleted or excreted in your model?
Great questions - of course this is a theory and the validity of any idea is based on the experiment. I've tried to find studies showing elevated or depleted levels of AMPK in the obese and have not found any - not saying they are out there, but I've just not been able to dig them up yet. I have found some studies linking diabetes to reduce AMPK, but not obesity itself. Not saying they aren't out there and I think if anyone has them on this board, it may be you, so I expect you will save me some searching and show me up haha.
I have found studies showing that AMPK is elevated in the brains of Alzheimer's patients.
I have found studies showing that AMPK does NOT protect against weight gain during over-feeding and, conversely, the reduced AMPK mice (through gene deletion) had better insulin sensitivity than normal mice with almost a 2-fold increase in glucose uptake.
In another angle, it appears that AMPK is not necessary for gluconeogenesis, but plays a critical role in metabolic flux (tying it back to PDK).
The second question is partially answered in the info above - gluconeogenesis or something along those lines. There's chemistry magic involved in the theory at the moment, admittedly, but if I have to convert fat to carbs just to burn them = double your metabolism.
I guess my main question here is what is the rationale behind looking into this?
if it’s genuinely to explore the way the human body works and make advances in our understanding of these mechanisms then fair enough.
if it’s to actually lose weight/fat/mass then why? We have tried and tested methods that do work for even those currently obese (you know my background).
I definitely don’t know enough to say if this theory would or wouldn’t work but I do know that the sheer number of interactions involved mean that unintended consequences would be pretty likely imo. For example maybe you inhibit ampk excessively but that spikes the hell out of cortisol which we know causes fat gain
(literally just giving an example to make a point, not one I’ve considered the science behind).
Well, it's to explore the ideas on the largest level. Basically, I think there's a lot of diet advice out there that's just NOT really accurate - like "metabolic slowdown", and lots of things that we do that seem effective, but are unknowingly damaging.
For instance, take the keto diet and apply my theories above. You would come to the conclusion that, of course it works - you have avoided the broken machinery altogether. If you cannot metabolize carbohydrates, then not eating them will avoid the issue.
But hey, if the reason you cannot metabolize carbohydrates has more to do with the fact that you're obese and you have too much PDK in your system to efficiently burn carbohydrates - then going on a keto diet will just further increase PDK, make your issue worse, and make it more likely you gain the weight back when you are all over. And also make it harder for you to lose the weight the second time around.
To add insult to injury - you've damaged the pathway that burns mass the quickest in favor of a pathway that, by design, conserves mass (giving the appearance of metabolic slowdown).
And so that person looks at a keto diet as the greatest thing because it made them lose weight, but then can't seem to keep the weight off and doesn't know what to do.
And, I think you're right with the final paragraph - there are a lot of factors here. And I think it's more complicated than "AMPK promotes lipolysis and inhibits mTOR"...I guess that's what I'm getting at on some level too. From a certain angle, AMPK may actually make fat loss harder and preserve mass.
Like you've said, everyone who is into building muscle AND longevity sees AMPK as kind of a mixed bag - but what if it wasn't that cut and dry. What if AMPK actually had a role in preserving muscle during low energy states (by turning on fat burning - if you're buning fat preferentially, you're going to spare muscle more than if you're burning carbs) - but also prevents the addition of new muscle under that state?
I'm not sure if it's really to directly lose weight, as much as to maybe understand how to keep it off or what prevents people from keeping it off and improve the details of how things work. And then take your link you provided above and figure out how to implement it into an appropriate strategy that doesn't obliterate it, but gets it back to normal.